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Tsukiyama N, Tanaka Y, Yamane H, Tanimine N, Kuroda S, Tahara H, Ohira M, Ide K, Kobayashi T, Ohdan H. Impacts of high mobility group box protein 1 gene polymorphisms on morbidity and mortality after living donor liver transplantation. Transpl Immunol 2025; 90:102225. [PMID: 40157616 DOI: 10.1016/j.trim.2025.102225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 03/25/2025] [Accepted: 03/25/2025] [Indexed: 04/01/2025]
Abstract
We investigated the effect of single-nucleotide polymorphisms (SNPs) in the high mobility group box 1 (HMGB1) gene on morbidity and mortality after liver transplantation (LT). Among 120 LT recipients and their living donors, the genotypes of HMGB1, and the SNPs rs2249825, rs1045411, rs1412125, and rs1360485 were determined. There were no significant associations between these four SNPs and the incidence of rejection or mortality. However, the incidence of early allograft dysfunction (EAD) (n = 43), which presents as functional insufficiency within 1 week of LT, was significantly higher in recipients with the GC + CC allele of rs2249825 (n = 17/34) than in those with the GG allele (n = 26/86) (p = 0.044). Although the impact of donor HMGB1 SNPs on the incidence of EAD was not statistically significant, recipients with the GC + CC allele of rs2249825 who received liver grafts from donors with the same genotype had the highest incidence of EAD (p = 0.052). In contrast, the donor TC + CC allele of rs1412125 was an independent risk factor for the development of sepsis (n = 33) in LT recipient (OR = 3.05, 95 % CI = 1.18-7.87, p = 0.021). Thus, the SNPs of the HMGB1 gene in either recipients or donors were not associated with mortality but influenced the incidence of EAD and sepsis, likely being a predictive biomarker for the risk of serious complications after LT.
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Affiliation(s)
- Naofumi Tsukiyama
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | - Hiroaki Yamane
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Naoki Tanimine
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Shintaro Kuroda
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Hiroyuki Tahara
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Kentaro Ide
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
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Tanaka K, Uchida Y, Kadono K, Kageyama S, Kawamoto H, Ito M, Kidoguchi Y, Saga K, Kojima H, Hirao H, Nakamura K, Taura K, Terajima H, Watanabe T, Hatano E. Recipient toll-like receptor 4 determines the outcome of ischemia-reperfusion injury in steatotic liver transplantation in mice. Am J Transplant 2025:S1600-6135(25)00108-X. [PMID: 40064295 DOI: 10.1016/j.ajt.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/16/2025] [Accepted: 03/04/2025] [Indexed: 04/01/2025]
Abstract
Toll-like receptor 4 (TLR4) plays a crucial role in ischemia-reperfusion injury (IRI) after liver transplantation (LT). However, the role of TLR4 in the context of steatotic grafts remains unclear. In this study, we developed a mouse model to explore IRI mechanisms in steatotic LT using TLR4 knockout mice as recipients. We successfully transplanted steatotic grafts with approximately 35% macrosteatosis and 5 hours of cold storage. Compared to normal LT, steatotic LT resulted in significantly higher serum level of alanine aminotransferase and high mobility group box 1 (HMGB1), higher transcriptional expression of inflammatory markers (C-X-C motif chemokine ligand 2, caspase-1, and caspase-11), and increased infiltration of CD11b-positive cells, correlating with lower survival. Serum HMGB1 and cleaved caspase-3 activation peaked earlier than serum alanine aminotransferase, with cold-stored steatotic grafts releasing more HMGB1. Notably, TLR4 knockout recipients demonstrated improved survival, attenuated inflammatory response, and reduced apoptosis. These findings suggest that TLR4 deficiency in recipients ameliorates IRI in steatotic LT, highlighting the importance of recipient immune modulation in mitigating steatotic graft injury.
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Affiliation(s)
- Kosuke Tanaka
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Yoichiro Uchida
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan.
| | - Kentaro Kadono
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shoichi Kageyama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Kawamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masaaki Ito
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuki Kidoguchi
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenichi Saga
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidenobu Kojima
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hirofumi Hirao
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Nakamura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Hiroaki Terajima
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, Osaka, Japan
| | - Takeshi Watanabe
- Division of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Song Z, Han H, Ge X, Das S, Desert R, Athavale D, Chen W, Komakula SSB, Lantvit D, Nieto N. Deficiency of neutrophil high-mobility group box-1 in liver transplant recipients exacerbates early allograft injury in mice. Hepatology 2023; 78:771-786. [PMID: 37016762 DOI: 10.1097/hep.0000000000000346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 02/10/2023] [Indexed: 04/06/2023]
Abstract
BACKGROUND AND AIMS Early allograft dysfunction (EAD) is a severe event leading to graft failure after liver transplant (LT). Extracellular high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern that contributes to hepatic ischemia-reperfusion injury (IRI). However, the contribution of intracellular HMGB1 to LT graft injury remains elusive. We hypothesized that intracellular neutrophil-derived HMGB1 from recipients protects from post-LT EAD. APPROACH AND RESULTS We generated mice with conditional ablation or overexpression of Hmgb1 in hepatocytes, myeloid cells, or both. We performed LTs and injected lipopolysaccharide (LPS) to evaluate the effect of intracellular HMGB1 in EAD. Ablation of Hmgb1 in hepatocytes and myeloid cells of donors and recipients exacerbated early allograft injury after LT. Ablation of Hmgb1 from liver grafts did not affect graft injury; however, lack of Hmgb1 from recipient myeloid cells increased reactive oxygen species (ROS) and inflammation in liver grafts and exacerbated injury. Neutrophils lacking HMGB1 were more activated, showed enhanced pro-oxidant and pro-inflammatory signatures, and reduced biosynthesis and metabolism of inositol polyphosphates (InsPs). On LT reperfusion or LPS treatment, there was significant neutrophil mobilization and infiltration into the liver and enhanced production of ROS and pro-inflammatory cytokines when intracellular Hmgb1 was absent. Depletion of neutrophils using anti-Ly6G antibody attenuated graft injury in recipients with myeloid cell Hmgb1 ablation. CONCLUSIONS Neutrophil HMGB1 derived from recipients is central to regulate their activation, limits the production of ROS and pro-inflammatory cytokines, and protects from early liver allograft injury.
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Affiliation(s)
- Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | | | - Daniel Lantvit
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
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Beetz O, Cammann S, Weigle CA, Sieg L, Eismann H, Johanning K, Falk CS, Krech T, Oldhafer F, Vondran FWR. Interleukin-18 and High-Mobility-Group-Protein B1 are Early and Sensitive Indicators for Cell Damage During Normothermic Machine Perfusion after Prolonged Cold Ischemic Storage of Porcine Liver Grafts. Transpl Int 2022; 35:10712. [PMID: 36338535 PMCID: PMC9630326 DOI: 10.3389/ti.2022.10712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/04/2022] [Indexed: 11/22/2022]
Abstract
In the era of organ machine perfusion, experimental models to optimize reconditioning of (marginal) liver grafts are needed. Although the relevance of cytokine signatures in liver transplantation has been analyzed previously, the significance of molecular monitoring during normothermic machine perfusion (NMP) remains elusive. Therefore, we developed a porcine model of cold ischemic liver graft injury after prolonged static cold storage (SCS) and subsequent NMP: Livers obtained from ten minipigs underwent NMP for 6 h directly after procurement (control group) or after 20 h of SCS. Grafts after prolonged SCS showed significantly elevated AST, ALT, GLDH and GGT perfusate concentrations, and reduced lactate clearance. Bile analyses revealed reduced bile production, reduced bicarbonate and elevated glucose concentrations after prolonged SCS. Cytokine analyses of graft perfusate simultaneously demonstrated an increase of pro-inflammatory cytokines such as Interleukin-1α, Interleukin-2, and particularly Interleukin-18. The latter was the only significantly elevated cytokine compared to controls, peaking as early as 2 h after reperfusion (11,012 ng/ml vs. 1,493 ng/ml; p = 0.029). Also, concentrations of High-Mobility-Group-Protein B1 were significantly elevated after 2 h of reperfusion (706.00 ng/ml vs. 148.20 ng/ml; p < 0.001) and showed positive correlations with AST (r2 = 0.846) and GLDH (r2 = 0.918) levels. Molecular analyses during reconditioning of liver grafts provide insights into the degree of inflammation and cell damage and could thereby facilitate future interventions during NMP reducing acute and chronic graft injury.
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Affiliation(s)
- Oliver Beetz
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Sebastian Cammann
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Clara A. Weigle
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Lion Sieg
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
| | - Hendrik Eismann
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
| | - Kai Johanning
- Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany
| | - Christine S. Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research, DZIF, TTU-IICH Braunschweig Site, Hannover, Germany
- German Center for Lung Research DZL, BREATH, Hannover, Germany
| | - Till Krech
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Felix Oldhafer
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Florian W. R. Vondran
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
- *Correspondence: Florian W. R. Vondran, , orcid.org/0000-0001-8355-5017
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Dai Q, Xie D, Zhang C, Zhu L, Xu Y, Li K, Hao W, Yin H. Osthole Blocks HMGB1 Release From the Nucleus and Confers Protective Effects Against Renal Ischemia-Reperfusion Injury. Front Physiol 2022; 12:735425. [PMID: 35002751 PMCID: PMC8727455 DOI: 10.3389/fphys.2021.735425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/20/2021] [Indexed: 11/13/2022] Open
Abstract
Renal ischemia-reperfusion (IR) is one of the main causes of renal injury. In severe cases with serious consequences, IR-related renal damage progresses rapidly and can even lead to acute renal failure. Its clinical treatment is currently difficult. According to various studies at home and abroad, HMGB1 is released from the nucleus into the cytoplasm or extracellular space by damaged parenchymal cells during ischemia and hypoxia, and this plays an important role in the initiation of reperfusion injury as an early inflammatory factor and is closely related to the occurrence and development of renal diseases. In recent years, the protective effect of osthole on IR of tissues and organs has been a key topic among clinical researchers. Osthole can inhibit the inflammatory response, reduce cell apoptosis the progression, and improve the prognosis of IR, thus protecting the kidney. During the development of renal IR, finding a mechanism through which the osthole blocks the release of HMGB1 from the nucleus would be helpful in detecting targets for clinical treatment.
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Affiliation(s)
- Qing Dai
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China.,North Sichuan Medical College, Nanchong, China
| | - Deqiong Xie
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Chenli Zhang
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Lei Zhu
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Ying Xu
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Kui Li
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Wen Hao
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
| | - Hefei Yin
- Department of Nephrology, The Second People's Hospital of Yibin, Yibin, China
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Lonati C, Schlegel A, Battistin M, Merighi R, Carbonaro M, Dongiovanni P, Leonardi P, Zanella A, Dondossola D. Effluent Molecular Analysis Guides Liver Graft Allocation to Clinical Hypothermic Oxygenated Machine Perfusion. Biomedicines 2021; 9:biomedicines9101444. [PMID: 34680561 PMCID: PMC8533371 DOI: 10.3390/biomedicines9101444] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/30/2021] [Accepted: 10/05/2021] [Indexed: 01/14/2023] Open
Abstract
Hypothermic-oxygenated-machine-perfusion (HOPE) allows assessment/reconditioning of livers procured from high-risk donors before transplantation. Graft referral to HOPE mostly depends on surgeons' subjective judgment, as objective criteria are still insufficient. We investigated whether analysis of effluent fluids collected upon organ flush during static-cold-storage can improve selection criteria for HOPE utilization. Effluents were analyzed to determine cytolysis enzymes, metabolites, inflammation-related mediators, and damage-associated-molecular-patterns. Molecular profiles were assessed by unsupervised cluster analysis. Differences between "machine perfusion (MP)-yes" vs. "MP-no"; "brain-death (DBD) vs. donation-after-circulatory-death (DCD)"; "early-allograft-dysfunction (EAD)-yes" vs. "EAD-no" groups, as well as correlation between effluent variables and transplantation outcome, were investigated. Livers assigned to HOPE (n = 18) showed a different molecular profile relative to grafts transplanted without this procedure (n = 21, p = 0.021). Increases in the inflammatory mediators PTX3 (p = 0.048), CXCL8/IL-8 (p = 0.017), TNF-α (p = 0.038), and ANGPTL4 (p = 0.010) were observed, whereas the anti-inflammatory cytokine IL-10 was reduced (p = 0.007). Peculiar inflammation, cell death, and coagulation signatures were observed in fluids collected from DCD livers compared to those from DBD grafts. AST (p = 0.034), ALT (p = 0.047), and LDH (p = 0.047) were higher in the "EAD-yes" compared to the "EAD-no" group. Cytolysis markers and hyaluronan correlated with recipient creatinine, AST, and ICU stay. The study demonstrates that effluent molecular analysis can provide directions about the use of HOPE.
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Affiliation(s)
- Caterina Lonati
- Center for Preclinical Research, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (M.B.); (R.M.); (D.D.)
- Correspondence: ; Tel.: +39-0255033318
| | - Andrea Schlegel
- Hepatobiliary Unit, Careggi University Hospital, University of Florence, 50139 Florence, Italy;
- Swiss HPB and Transplant Center, Department of Visceral Surgery and Transplantation, University Hospital Zurich, 8000 Zurich, Switzerland
| | - Michele Battistin
- Center for Preclinical Research, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (M.B.); (R.M.); (D.D.)
| | - Riccardo Merighi
- Center for Preclinical Research, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (M.B.); (R.M.); (D.D.)
| | - Margherita Carbonaro
- General and Liver Transplant Sugery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy;
| | - Patrizia Leonardi
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; (P.L.); (A.Z.)
| | - Alberto Zanella
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; (P.L.); (A.Z.)
- Department of Anesthesia and Critical Care, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Daniele Dondossola
- Center for Preclinical Research, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (M.B.); (R.M.); (D.D.)
- General and Liver Transplant Sugery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; (P.L.); (A.Z.)
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Sun J, He Y, Bai L, Wang Z, Cao Z, Shao Y, Zhao J. An Analysis of the Risk Factors for New-Onset Diabetes Mellitus After Liver Transplantation. Int J Gen Med 2021; 14:4783-4792. [PMID: 34466023 PMCID: PMC8402980 DOI: 10.2147/ijgm.s324462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/11/2021] [Indexed: 11/23/2022] Open
Abstract
Objective To investigate the risk factors related to new-onset diabetes mellitus (NODM) and the significance of IL-6. Methods A retrospective analysis was conducted on clinical data from 64 patients who received either a living donor liver transplantation or a donation after circulatory death from September 2013 to October 2020 and attended regular follow-up visits for six or more months. During follow-up, patients were randomized into groups and followed up until the completion of the study or the death of the patient. Results The incidence of NODM was 31.25% (n = 20). The median age in the NODM group was 52.15 years (p < 0.01). Age (OR = 1.089; 95% CI: 0.0211-0.1495, p = 0.003) and elevated preoperative IL-6 (OR = 1.122; 95% CI: 0.0619-0.1677, p = 0.029) were found to be independent risk factors for NODM. HBV-induced liver cirrhosis, warm ischemia time (WIT), body mass index (BMI), and high preoperative fasting blood glucose (FBG) were also found to be risk factors for NODM. The recipient had a higher risk of NODM if the donor had a high BMI and poor hepatic function. The concentrations of IL-6, procalcitonin (PCT), FBG, and tacrolimus (TAC) in the first month postoperatively were significantly higher in the NODM group than in the NO-NODM group. The survival rate of the patients was not affected by NODM. Conclusion HBV-induced liver cirrhosis, WIT, BMI, and high preoperative FBG levels are risk factors for NODM, and age and preoperative IL-6 levels are independent risk factors. To a certain extent, higher BMI and poor hepatic function had reference significance for the incidence of NODM. Patients with a high concentration of FBG, IL-6, and TAC in the first month postoperatively had an increased risk of suffering from NODM.
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Affiliation(s)
- Jushan Sun
- Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Yibiao He
- Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Lei Bai
- Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Zhipeng Wang
- Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Zhu Cao
- Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Yingmei Shao
- Xinjiang Uyghur Autonomous Region Clinical Research Center for Echinococcosis and Hepatobiliary Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Jinming Zhao
- Department of Liver and Laparoscopic Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
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Ye Z, Jia J, Lv Z, Zheng S. Identification of High-Mobility Group Box 1 (HMGB1) Expression as a Potential Predictor of Rejection and Poor Prognosis After Liver Transplantation. Ann Transplant 2021; 26:e931625. [PMID: 34282108 PMCID: PMC8306885 DOI: 10.12659/aot.931625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Acute cellular rejection (ACR) frequently occurs after liver transplantation (LT) and can result in permanent damage of the liver allograft. Specific and sensitive biomarkers for predicting and monitoring ACR are vital for guiding post-transplantation care. In the present study, we aimed to investigate the function of high-mobility group box 1 (HMGB1) in predicting ACR and prognosis after LT. MATERIAL AND METHODS A total of 113 LT recipients were enrolled in the study, including 62 patients in an ACR group and 51 patients in a non-rejection group. Using tissues from the 113 patients, HMGB1 expression was examined by immunohistochemistry, and the total score for HMGB1 expression was calculated by multiplying the percentage of immunoreactive cells score and the staining intensity score. We then analyzed the association between HMGB1 expression and clinical features. Finally, the function of HMGB1 in predicting the prognosis of LT was determined using Kaplan-Meier (K-M) survival and Cox multivariate analyses. RESULTS Immunohistochemical staining results demonstrated that the expression of HMGB1 was significantly increased in the ACR group, compared with that in the non-rejection group (P<0.05). Clinical characteristic analysis revealed that high HMGB1 levels were related to ACR (P<0.05). Moreover, K-M survival analysis showed that patients with high HMGB1 expression displayed poorer prognosis (P<0.05). Cox multivariate analysis demonstrated that HMGB1 was an independent prognostic predictor for post-LT survival (odds ratio, 3.283; P=0.008). CONCLUSIONS LT recipients' HMGB1 levels may be a useful and noninvasive biomarker for the prediction of ACR and prognosis after LT.
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Affiliation(s)
- Zhou Ye
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang, China (mainland)
| | - Junjun Jia
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang, China (mainland)
| | - Zhen Lv
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang, China (mainland)
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland).,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang, China (mainland)
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Sosa RA, Terry AQ, Kaldas FM, Jin YP, Rossetti M, Ito T, Li F, Ahn RS, Naini BV, Groysberg VM, Zheng Y, Aziz A, Nevarez-Mejia J, Zarrinpar A, Busuttil RW, Gjertson DW, Kupiec-Weglinski JW, Reed EF. Disulfide High-Mobility Group Box 1 Drives Ischemia-Reperfusion Injury in Human Liver Transplantation. Hepatology 2021; 73:1158-1175. [PMID: 32426849 PMCID: PMC8722704 DOI: 10.1002/hep.31324] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 04/16/2020] [Accepted: 04/19/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Sterile inflammation is a major clinical concern during ischemia-reperfusion injury (IRI) triggered by traumatic events, including stroke, myocardial infarction, and solid organ transplantation. Despite high-mobility group box 1 (HMGB1) clearly being involved in sterile inflammation, its role is controversial because of a paucity of patient-focused research. APPROACH AND RESULTS Here, we examined the role of HMGB1 oxidation states in human IRI following liver transplantation. Portal blood immediately following allograft reperfusion (liver flush; LF) had increased total HMGB1, but only LF from patients with histopathological IRI had increased disulfide-HMGB1 and induced Toll-like receptor 4-dependent tumor necrosis factor alpha production by macrophages. Disulfide HMGB1 levels increased concomitantly with IRI severity. IRI+ prereperfusion biopsies contained macrophages with hyperacetylated, lysosomal disulfide-HMGB1 that increased postreperfusion at sites of injury, paralleling increased histone acetyltransferase general transcription factor IIIC subunit 4 and decreased histone deacetylase 5 expression. Purified disulfide-HMGB1 or IRI+ blood stimulated further production of disulfide-HMGB1 and increased proinflammatory molecule and cytokine expression in macrophages through a positive feedback loop. CONCLUSIONS These data identify disulfide-HMGB1 as a mechanistic biomarker of, and therapeutic target for, minimizing sterile inflammation during human liver IRI.
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Affiliation(s)
- Rebecca A. Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Allyson Q. Terry
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Fady M. Kaldas
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Yi-Ping Jin
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Maura Rossetti
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Takahiro Ito
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Fang Li
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Richard S. Ahn
- Institute of Quantitative and Computational Biosciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Bita V. Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Victoria M. Groysberg
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Ying Zheng
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Antony Aziz
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Jessica Nevarez-Mejia
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Ali Zarrinpar
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - David W. Gjertson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Department of Biostatistics, School of Public Health at UCLA, Los Angeles, CA, 90095, USA
| | - Jerzy W. Kupiec-Weglinski
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
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10
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Han H, Desert R, Das S, Song Z, Athavale D, Ge X, Nieto N. Danger signals in liver injury and restoration of homeostasis. J Hepatol 2020; 73:933-951. [PMID: 32371195 PMCID: PMC7502511 DOI: 10.1016/j.jhep.2020.04.033] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 04/08/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]
Abstract
Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice.
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Affiliation(s)
- Hui Han
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Sukanta Das
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, 840 S. Wood St., Suite 1020N, MC 787, Chicago, IL 60612, USA.
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11
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Vijayakumar EC, Bhatt LK, Prabhavalkar KS. High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics. Curr Drug Targets 2020; 20:1474-1485. [PMID: 31215389 DOI: 10.2174/1389450120666190618125100] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 05/29/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023]
Abstract
High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.
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Affiliation(s)
- Eyaldeva C Vijayakumar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Lokesh Kumar Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Kedar S Prabhavalkar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
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12
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Stefanello ST, de Carvalho NR, Reis SB, Soares FAA, Barcelos RP. Acetaminophen Oxidation and Inflammatory Markers - A Review of Hepatic Molecular Mechanisms and Preclinical Studies. Curr Drug Targets 2020; 21:1225-1236. [PMID: 32386489 DOI: 10.2174/1389450121666200510014418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/06/2020] [Accepted: 02/21/2020] [Indexed: 11/22/2022]
Abstract
Acetaminophen is a widely used analgesic for pain management, especially useful in chronic diseases, such as rheumatoid arthritis. However, easy access to this medicine has increased the occurrence of episodes of poisoning. Patients often develop severe liver damage, which may quickly lead to death. Consequently, numerous studies have been conducted to identify new biomarkers that allow the prediction of the degree of acetaminophen intoxication and thus intervene in a timely manner to save patients' lives. This review highlights the main mechanisms of the induction and progression of liver damage arising from acetaminophen poisoning. In addition, we have discussed the possibility of using new clinical biomarkers for detecting acetaminophen poisoning.
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Affiliation(s)
- Silvio Terra Stefanello
- Programa de Pos-Graduacao em Bioquimica Toxicologica, Centro de Ciencias Naturais e Exatas (CCNE), Universidade Federal de Santa Maria, Brazil
| | | | - Simone Beder Reis
- Institudo de Ciencias Biologicas (ICB), Programa de Posgraduacao em Bioexperimentacao, Universidade de Passo Fundo, Passo Fundo, Brazil
| | - Felix Alexandre Antunes Soares
- Programa de Pos-Graduacao em Bioquimica Toxicologica, Centro de Ciencias Naturais e Exatas (CCNE), Universidade Federal de Santa Maria, Brazil
| | - Rômulo Pillon Barcelos
- Programa de Pos-Graduacao em Bioquimica Toxicologica, Centro de Ciencias Naturais e Exatas (CCNE), Universidade Federal de Santa Maria, Brazil
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13
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Faria LC, Andrade AMF, Trant CGMC, Lima AS, Machado PAB, Porto RD, Andrade MVM. Circulating levels of High‐mobility group box 1 protein and nucleosomes are associated with outcomes after liver transplant. Clin Transplant 2020; 34:e13869. [DOI: 10.1111/ctr.13869] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 03/08/2020] [Accepted: 03/29/2020] [Indexed: 01/21/2023]
Affiliation(s)
- Luciana C. Faria
- Departamento de Clínica Médica Faculdade de Medicina Universidade Federal de Minas Gerais Belo Horizonte Brasil
- Grupo de Transplante de Órgãos Instituto Alfa de Gastroenterologia Hospital das Clínicas Universidade Federal de Minas Gerais Belo Horizonte Brasil
| | - Antônio Márcio F. Andrade
- Grupo de Transplante de Órgãos Instituto Alfa de Gastroenterologia Hospital das Clínicas Universidade Federal de Minas Gerais Belo Horizonte Brasil
| | - Cyntia G. M. C. Trant
- Laboratório de Fisiopatologia Cirúrgica Faculdade de Medicina Universidade Federal de Minas Gerais Belo Horizonte Brasil
| | - Agnaldo S. Lima
- Grupo de Transplante de Órgãos Instituto Alfa de Gastroenterologia Hospital das Clínicas Universidade Federal de Minas Gerais Belo Horizonte Brasil
- Departamento de Cirurgia Faculdade de Medicina Universidade Federal de Minas Gerais Belo Horizonte Brasil
| | - Pedro A. B. Machado
- Faculdade de Medicina Universidade Federal de Minas Gerais Belo Horizonte Brasil
| | - Rodrigo D. Porto
- Faculdade de Medicina Universidade Federal de Minas Gerais Belo Horizonte Brasil
| | - Marcus Vinícius M. Andrade
- Departamento de Clínica Médica Faculdade de Medicina Universidade Federal de Minas Gerais Belo Horizonte Brasil
- Laboratório de Fisiopatologia Cirúrgica Faculdade de Medicina Universidade Federal de Minas Gerais Belo Horizonte Brasil
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14
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Rafikov R, Nair V, Sinari S, Babu H, Sullivan JC, Yuan JXJ, Desai AA, Rafikova O. Gender Difference in Damage-Mediated Signaling Contributes to Pulmonary Arterial Hypertension. Antioxid Redox Signal 2019; 31:917-932. [PMID: 30652485 PMCID: PMC6765065 DOI: 10.1089/ars.2018.7664] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Aims: Pulmonary arterial hypertension (PAH) is a progressive lethal disease with a known gender dimorphism. Female patients are more susceptible to PAH, whereas male patients have a lower survival rate. Initial pulmonary vascular damage plays an important role in PAH pathogenesis. Therefore, this study aimed at investigating the role of gender in activation of apoptosis/necrosis-mediated signaling pathways in PAH. Results: The media collected from pulmonary artery endothelial cells (PAECs) that died by necrosis or apoptosis were used to treat naive PAECs. Necrotic cell death stimulated phosphorylation of toll-like receptor 4, accumulation of interleukin 1 beta, and expression of E-selectin in a redox-dependent manner; apoptosis did not induce any of these effects. In the animal model of severe PAH, the necrotic marker, high mobility group box 1 (HMGB1), was visualized in the pulmonary vascular wall of male but not female rats. This vascular necrosis was associated with male-specific redox changes in plasma, activation of the same inflammatory signaling pathway seen in response to necrosis in vitro, and an increased endothelial-leukocyte adhesion in small pulmonary arteries. In PAH patients, gender-specific changes in redox homeostasis correlated with the prognostic marker, B-type natriuretic peptide. Males had also shown elevated circulating levels of HMGB1 and pro-inflammatory changes. Innovation: This study discovered the role of gender in the initiation of damage-associated signaling in PAH and highlights the importance of the gender-specific approach in PAH therapy. Conclusion: In PAH, the necrotic cell death is augmented in male patients compared with female patients. Factors released from necrotic cells could alter redox homeostasis and stimulate inflammatory signaling pathways.
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Affiliation(s)
- Ruslan Rafikov
- Division of Endocrinology, Department of Medicine, University of Arizona, Tucson, Arizona
| | - Vineet Nair
- Division of Cardiology, Sarver Heart Center, University of Arizona, Tucson, Arizona
| | - Shripad Sinari
- Center for Biomedical Informatics and Biostatistics, University of Arizona, Tucson, Arizona
| | | | | | - Jason X-J Yuan
- Division of Translational and Regenerative Medicine, University of Arizona, Tucson, Arizona
| | - Ankit A Desai
- Division of Cardiology, Sarver Heart Center, University of Arizona, Tucson, Arizona
| | - Olga Rafikova
- Division of Endocrinology, Department of Medicine, University of Arizona, Tucson, Arizona
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15
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Shi S, Verstegen MMA, Mezzanotte L, de Jonge J, Löwik CWGM, van der Laan LJW. Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective. Liver Transpl 2019; 25:1091-1104. [PMID: 31077562 PMCID: PMC6617733 DOI: 10.1002/lt.25488] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 04/22/2019] [Indexed: 12/13/2022]
Abstract
Cell death is a natural process for the turnover of aged cells, but it can also arise as a result of pathological conditions. Cell death is recognized as a key feature in both acute and chronic hepatobiliary diseases caused by drug, alcohol, and fat uptake; by viral infection; or after surgical intervention. In the case of chronic disease, cell death can lead to (chronic) secondary inflammation, cirrhosis, and the progression to liver cancer. In liver transplantation, graft preservation and ischemia/reperfusion injury are associated with acute cell death. In both cases, so-called programmed cell death modalities are involved. Several distinct types of programmed cell death have been described of which apoptosis and necroptosis are the most well known. Parenchymal liver cells, including hepatocytes and cholangiocytes, are susceptible to both apoptosis and necroptosis, which are triggered by distinct signal transduction pathways. Apoptosis is dependent on a proteolytic cascade of caspase enzymes, whereas necroptosis induction is caspase-independent. Moreover, different from the "silent" apoptotic cell death, necroptosis can cause a secondary inflammatory cascade, so-called necroinflammation, triggered by the release of various damage-associated molecular patterns (DAMPs). These DAMPs activate the innate immune system, leading to both local and systemic inflammatory responses, which can even cause remote organ failure. Therapeutic targeting of necroptosis by pharmacological inhibitors, such as necrostatin-1, shows variable effects in different disease models.
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Affiliation(s)
- Shaojun Shi
- Department of SurgeryErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
| | | | - Laura Mezzanotte
- Department of RadiologyErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
| | - Jeroen de Jonge
- Department of SurgeryErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
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16
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Association between Early Acute Respiratory Distress Syndrome after Living-Donor Liver Transplantation and Perioperative Serum Biomarkers: The Role of Club Cell Protein 16. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8958069. [PMID: 31111072 PMCID: PMC6487165 DOI: 10.1155/2019/8958069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 03/27/2019] [Indexed: 12/13/2022]
Abstract
Background Acute respiratory distress syndrome (ARDS) after living-donor liver transplantation (LDLT) is not uncommon, but it lacks the biomarkers for early detection. Club cell protein 16 (CC16), high-motility group box 1 protein (HMGB1), interleukin-1β (IL-1β), and IL-10 have been reported as relevant to the development of ARDS. However, they have not been investigated during LDLT. Methods Seventy-three consecutive recipients undergoing LDLT were enrolled and received the same perioperative care plan. Perioperative serum CC16, HMGB1, IL-1β, and IL-10 levels were measured at the pretransplant state, 30 minutes after reperfusion, postoperative day 1 (POD1), and POD3. ARDS was diagnosed according to the 2012 Berlin definition. Results Of the 73 recipients, 13 developed ARDS with significantly longer durations of mechanical ventilation and intensive care unit stay. Serum CC16 levels on POD1 increased significantly from the pretransplant state in the ARDS group but not in the non-ARDS group. Pretransplant serum CC16 levels were also higher in the ARDS group. The area under the receiver operating characteristic curves for POD1 serum CC16 levels used to discriminate ARDS was 0.803 (95% confidence interval: 0.679 to 0.895; p < 0.001). By comparison, HMGB1, IL-1β, and IL-10 were not associated with ARDS after LDLT. Conclusion The higher pretransplant serum CC16 level and its increased level on POD1 were associated with the development of early ARDS after LDLT. This trial is registered with NCT01936545, 27 August 2013.
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17
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Yu S, Zhou X, Xiang H, Wang S, Cui Z, Zhou J. Resveratrol Reduced Liver Damage After Liver Resection in a Rat Model by Upregulating Sirtuin 1 (SIRT1) and Inhibiting the Acetylation of High Mobility Group Box 1 (HMGB1). Med Sci Monit 2019; 25:3212-3220. [PMID: 31041919 PMCID: PMC6507495 DOI: 10.12659/msm.913937] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Liver failure after resection for liver cancer is associated with increased patient mortality. This study aimed to investigate the mechanism of the protective effects of resveratrol, a natural plant-derived compound, on liver injury in a rat model of partial hepatectomy. Material/Methods Adult male Sprague-Dawley (SD) rats (n=60) were divided into the sham group (n=20), the liver resection group (n=20), and the liver resection plus resveratrol-treated group (n=20). Liver resection removed 2/3 of the liver resection; resveratrol was given at a dose of 30 mg/kg/day from one week before surgery until death. Liver injury was assessed by serum liver function tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl-transferase (γ-GT) and total bilirubin, histological examination of the rat liver, and liver cell apoptosis using the TUNEL assay. High mobility group box 1 (HMGB1) expression was measured by enzyme-linked immunoassay (ELISA). Sirtuin 1 (SIRT1) and acetylated HMGB1 (Ac-HMGB1) expression were detected by Western blot. Normal human liver cells and HepG2 liver cancer cells were incubated with acetylated HMGB1, and albumin production and ammonia elimination assays were performed. Results Resveratrol reduced postoperative liver injury as shown by reduced ALT, AST, γ-GT, and total bilirubin levels, maintained liver structure, and reduced cell apoptosis. Resveratrol treatment reduced the expression and acetylation levels of HMGB1 via the SIRT1 signaling pathway. Resveratrol reversed Ac-HMGB1 induced dysfunction in liver cells cultured in vitro. Conclusions Resveratrol reduced liver damage after liver resection in a rat model by upregulating SIRT1 and reducing the acetylation of HMGB1.
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Affiliation(s)
- Sheng Yu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (mainland)
| | - Xingliang Zhou
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA
| | - Hang Xiang
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA
| | - Shaoping Wang
- Department of Hepatobiliary Surgery, General Hospital of Guangzhou Military Command of People's Liberation Army, Guangzhou, Guangdong, China (mainland)
| | - Zhonglin Cui
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (mainland)
| | - Jie Zhou
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (mainland)
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18
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Constitutive release of CPS1 in bile and its role as a protective cytokine during acute liver injury. Proc Natl Acad Sci U S A 2019; 116:9125-9134. [PMID: 30979808 DOI: 10.1073/pnas.1822173116] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Carbamoyl phosphate synthetase-1 (CPS1) is the major mitochondrial urea cycle enzyme in hepatocytes. It is released into mouse and human blood during acute liver injury, where is has a short half-life. The function of CPS1 in blood and the reason for its short half-life in serum are unknown. We show that CPS1 is released normally into mouse and human bile, and pathologically into blood during acute liver injury. Other cytoplasmic and mitochondrial urea cycle enzymes are also found in normal mouse bile. Serum, bile, and purified CPS1 manifest sedimentation properties that overlap with extracellular vesicles, due to the propensity of CPS1 to aggregate despite being released primarily as a soluble protein. During liver injury, CPS1 in blood is rapidly sequestered by monocytes, leading to monocyte M2-polarization and homing to the liver independent of its enzyme activity. Recombinant CPS1 (rCPS1), but not control r-transferrin, increases hepatic macrophage numbers and phagocytic activity. Notably, rCPS1 does not activate hepatic macrophages directly; rather, it activates bone marrow and circulating monocytes that then home to the liver. rCPS1 administration prevents mouse liver damage induced by Fas ligand or acetaminophen, but this protection is absent in macrophage-deficient mice. Moreover, rCPS1 protects from acetaminophen-induced liver injury even when given therapeutically after injury induction. In summary, CPS1 is normally found in bile but is released by hepatocytes into blood upon liver damage. We demonstrate a nonenzymatic function of CPS1 as an antiinflammatory protective cytokine during acute liver injury.
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19
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Burlage LC, Bos S, Adelmeijer J, Sakai T, Porte RJ, Lisman T. Plasma From Patients Undergoing Liver Transplantation Is Resistant to Anticoagulant Activity of Soluble Thrombomodulin. Liver Transpl 2019; 25:252-259. [PMID: 30067306 PMCID: PMC6590179 DOI: 10.1002/lt.25318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 07/23/2018] [Indexed: 01/13/2023]
Abstract
Recombinant human soluble thrombomodulin (ART-123) is an anticoagulant and anti-inflammatory agent clinically used for treatment of disseminated intravascular coagulation. Preclinical studies have shown that ART-123 reduces hepatic ischemia/reperfusion. Although ART-123 may therefore have clinical benefit in orthotopic liver transplantation, the substantial alterations in the hemostatic system may complicate its use in this setting. Here, we studied the in vitro effect of ART-123 on coagulation of patients with end-stage liver disease undergoing liver transplantation. Ten patients with end-stage liver disease undergoing liver transplantation were included in this study. Plasma samples of 10 healthy individuals were included to establish reference values. Different concentrations of ART-123 were added to plasma samples, and peak thrombin generation and clot lysis times (CLTs) were determined. In patient samples, plasma was profoundly resistant to the anticoagulant action of ART-123, as reflected by significantly higher median inhibitory concentration (IC50 ) values of peak thrombin generation compared with controls. This might be partially explained by low levels of protein C, protein S, and elevated levels of factor VIII during transplantation. Intraoperative levels of thrombin activatable fibrinolysis inhibitor were significantly lower when compared with controls. However, ART-123-dependent prolongation of CLTs was not significantly different from healthy controls. In conclusion, this study suggests that ART-123 is unlikely to provoke bleeding in patients undergoing liver transplantation because proposed clinical dosages have a virtually absent anticoagulant effect in these patients. Clinical studies are required to confirm the safety of ART-123 and efficacy on alleviating ischemia/reperfusion injury during liver transplantation.
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Affiliation(s)
- Laura C. Burlage
- Section of HPB Surgery and Liver Transplantation,Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Sarah Bos
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Jelle Adelmeijer
- Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
| | - Takumi Sakai
- Development Planning, Clinical Department CenterAsahi Kasei Pharma CorporationTokyoJapan
| | | | - Ton Lisman
- Section of HPB Surgery and Liver Transplantation,Surgical Research Laboratory, Department of SurgeryUniversity Medical Center Groningen, University of GroningenGroningenthe Netherlands
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20
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van Golen RF, Reiniers MJ, Marsman G, Alles LK, van Rooyen DM, Petri B, Van der Mark VA, van Beek AA, Meijer B, Maas MA, Zeerleder S, Verheij J, Farrell GC, Luken BM, Teoh NC, van Gulik TM, Murphy MP, Heger M. The damage-associated molecular pattern HMGB1 is released early after clinical hepatic ischemia/reperfusion. Biochim Biophys Acta Mol Basis Dis 2019; 1865:1192-1200. [PMID: 30658161 DOI: 10.1016/j.bbadis.2019.01.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 12/21/2018] [Accepted: 01/11/2019] [Indexed: 12/31/2022]
Abstract
OBJECTIVE AND BACKGROUND Activation of sterile inflammation after hepatic ischemia/reperfusion (I/R) culminates in liver injury. The route to liver damage starts with mitochondrial oxidative stress and cell death during early reperfusion. The link between mitochondrial oxidative stress, damage-associate molecular pattern (DAMP) release, and sterile immune signaling is incompletely understood and lacks clinical validation. The aim of the study was to validate this relation in a clinical liver I/R cohort and to limit DAMP release using a mitochondria-targeted antioxidant in I/R-subjected mice. METHODS Plasma levels of the DAMPs high-mobility group box 1 (HMGB1), mitochondrial DNA, and nucleosomes were measured in 39 patients enrolled in an observational study who underwent a major liver resection with (N = 29) or without (N = 13) intraoperative liver ischemia. Circulating cytokine and neutrophil activation markers were also determined. In mice, the mitochondria-targeted antioxidant MitoQ was intravenously infused in an attempt to limit DAMP release, reduce sterile inflammation, and suppress I/R injury. RESULTS In patients, HMGB1 was elevated following liver resection with I/R compared to liver resection without I/R. HMGB1 levels correlated positively with ischemia duration and peak post-operative transaminase (ALT) levels. There were no differences in mitochondrial DNA, nucleosome, or cytokine levels between the two groups. In mice, MitoQ neutralized hepatic oxidative stress and decreased HMGB1 release by ±50%. MitoQ suppressed transaminase release, hepatocellular necrosis, and cytokine production. Reconstituting disulfide HMGB1 during reperfusion reversed these protective effects. CONCLUSION HMGB1 seems the most pertinent DAMP in clinical hepatic I/R injury. Neutralizing mitochondrial oxidative stress may limit DAMP release after hepatic I/R and reduce liver damage.
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Affiliation(s)
- Rowan F van Golen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Megan J Reiniers
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Gerben Marsman
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Lindy K Alles
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Derrick M van Rooyen
- Liver Research Group, Australian National University at The Canberra Hospital, Canberra, Australia
| | - Björn Petri
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary AB T2N 1N4, Alberta, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada
| | - Vincent A Van der Mark
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Tytgat Institute for Gastrointestinal and Liver Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Adriaan A van Beek
- Department of Cell Biology and Immunology, Wageningen University, Wageningen, the Netherlands
| | - Ben Meijer
- Department of Cell Biology and Immunology, Wageningen University, Wageningen, the Netherlands
| | - Martinus A Maas
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Sacha Zeerleder
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, University of Bern, Switzerland
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Geoffrey C Farrell
- Liver Research Group, Australian National University at The Canberra Hospital, Canberra, Australia
| | - Brenda M Luken
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Narci C Teoh
- Liver Research Group, Australian National University at The Canberra Hospital, Canberra, Australia
| | - Thomas M van Gulik
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Michael P Murphy
- Medical Research Council Mitochondrial Biology Unit, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Michal Heger
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China.
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Gaskell H, Ge X, Nieto N. High-Mobility Group Box-1 and Liver Disease. Hepatol Commun 2018; 2:1005-1020. [PMID: 30202816 PMCID: PMC6128227 DOI: 10.1002/hep4.1223] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 06/03/2018] [Indexed: 12/12/2022] Open
Abstract
High‐mobility group box‐1 (HMGB1) is a ubiquitous protein. While initially thought to be simply an architectural protein due to its DNA‐binding ability, evidence from the last decade suggests that HMGB1 is a key protein participating in the pathogenesis of acute liver injury and chronic liver disease. When it is passively released or actively secreted after injury, HMGB1 acts as a damage‐associated molecular pattern that communicates injury and inflammation to neighboring cells by the receptor for advanced glycation end products or toll‐like receptor 4, among others. In the setting of acute liver injury, HMGB1 participates in ischemia/reperfusion, sepsis, and drug‐induced liver injury. In the context of chronic liver disease, it has been implicated in alcoholic liver disease, liver fibrosis, nonalcoholic steatohepatitis, and hepatocellular carcinoma. Recently, specific posttranslational modifications have been identified that could condition the effects of the protein in the liver. Here, we provide a detailed review of how HMGB1 signaling participates in acute liver injury and chronic liver disease.
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Affiliation(s)
- Harriet Gaskell
- Department of Pathology University of Illinois at Chicago Chicago IL
| | - Xiaodong Ge
- Department of Pathology University of Illinois at Chicago Chicago IL
| | - Natalia Nieto
- Department of Pathology University of Illinois at Chicago Chicago IL.,Department of Medicine University of Illinois at Chicago Chicago IL
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22
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Houben P, Hohenberger R, Yamanaka K, Büchler MW, Schemmer P. Evaluation of Graft Effluent High Mobility Group Box-1 (HMGB-1) for Prediction of Outcome After Liver Transplantation. Ann Transplant 2018; 23:475-480. [PMID: 30002362 PMCID: PMC6248035 DOI: 10.12659/aot.909165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 02/28/2018] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Pre-transplant assessment of the graft for liver transplantation is crucial. Based on experimental data, this study was designed to assess both nuclear high mobility group box-1 (HMGB-1) protein and arginine-specific proteolytic activity (ASPA) in the graft effluent. MATERIAL AND METHODS In a non-interventional trial, both HMGB-1 and ASPA were measured in the effluent of 30 liver grafts after cold storage before transplantation. Values of HMGB-1 and ASPA levels were compared with established prognostic parameters such as the donor risk index, balance of risk score, and Donor-Model for End-Stage Liver Disease. RESULTS The early allograft dysfunction (EAD) was best predicted by recipient age (p=0.026) and HMGB-1 (p=0.031). HMGB -1 thresholds indicated the likelihood for initial non-function (1608 ng/ml, p=0.004) and EAD (580 ng/ml, p=0.017). The multivariate binary regression analysis showed a 21-fold higher (95% CI: 1.6-284.5, p=0.022) risk for EAD in cases with levels exceeding 580 ng/ml. The ASPA was lower in cases of initial non-function (p=0.028) but did not correlate with the rate of EAD (p=0.4). CONCLUSIONS This study demonstrates the feasibility of HMGB-1 detection in the graft effluent after cold storage. Along with conventional prognostic scores, it may be helpful to predict the early fate of a graft in human liver transplantation.
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Kageyama S, Nakamura K, Fujii T, Ke B, Sosa RA, Reed EF, Datta N, Zarrinpar A, Busuttil RW, Kupiec-Weglinski JW. Recombinant relaxin protects liver transplants from ischemia damage by hepatocyte glucocorticoid receptor: From bench-to-bedside. Hepatology 2018; 68:258-273. [PMID: 29350771 PMCID: PMC6033647 DOI: 10.1002/hep.29787] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 12/09/2017] [Accepted: 01/12/2018] [Indexed: 12/18/2022]
Abstract
UNLABELLED Hepatic ischemia-reperfusion injury (IRI) represents a major risk factor of early graft dysfunction and acute/chronic rejection as well as a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although glucocorticoid receptor (GR) signaling may enhance cytoprotective programs, clinical use of glucocorticoid is limited because of adverse effects, whereas clinical relevance of GR-facilitated cytoprotection in OLT remains unknown. We aimed to evaluate the significance of hepatic GR in clinical OLT and verify the impact of recombinant human relaxin (rhRLX), which may function as a GR agonist in a tissue/disease-specific manner. Fifty-one OLT patients were recruited under an institutional research board (IRB) protocol. Liver biopsies were collected after cold storage (presurgery) and 2 hours postreperfusion (before abdominal closure), followed by western blotting-assisted hepatic analyses. Forty-three percent of OLTs failed to increase GR perioperatively under surgical stress. Post-/pre-GR ratios at postoperative day 1 correlated negatively with serum aspartate aminotransferase (AST)/cleaved caspase-3 and positively with B-cell lymphoma-extra large (Bcl-xL)/B-cell lymphoma 2 (Bcl-2) levels. In a murine OLT model with extended (18-hour) cold storage, treatment with rhRLX ameliorated ischemia-reperfusion (IR) damage and improved survival while up-regulating hepatocyte GR and Bcl-xL/Bcl-2 expression in OLT. rhRLX-induced GR suppressed hepatocyte high-mobility group box 1 (HMGB1) translocation/release, accompanied by decreased Toll-like receptor 4 (TLR4)/receptor for advanced glycation end products (RAGE), suppressed interleukin 1 beta (IL1β), chemokine (C-C motif) ligand 2 (CCL2), C-X-C motif chemokine (CXCL)10, tumor necrosis factor alpha (TNFα), CXCL1, and CXCL2 levels, and attenuated neutrophil/macrophage accumulation in OLT. Inhibition of GR in hepatocyte culture and in OLT diminished rhRLX-mediated cytoprotection. CONCLUSION This translational study underscores the role of rhRLX-GR signaling as a regulator of hepatocellular protection against IR stress in OLT. In the context of a recent phase III clinical trial demonstrating positive outcomes of rhRLX in patients with acute heart failure, studies on rhRLX for the management of IRI in OLT recipients are warranted. (Hepatology 2018;68:258-273).
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Affiliation(s)
- Shoichi Kageyama
- The Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, University of California, Los Angeles, CA 90095
| | - Kojiro Nakamura
- The Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, University of California, Los Angeles, CA 90095
| | - Takehiro Fujii
- The Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, University of California, Los Angeles, CA 90095
| | - Bibo Ke
- The Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, University of California, Los Angeles, CA 90095
| | - Rebecca A Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095
| | - Nakul Datta
- The Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, University of California, Los Angeles, CA 90095
| | - Ali Zarrinpar
- The Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, University of California, Los Angeles, CA 90095
| | - Ronald W. Busuttil
- The Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, University of California, Los Angeles, CA 90095
| | - Jerzy W. Kupiec-Weglinski
- The Dumont-UCLA Transplant Center, Department of Surgery, Division of Liver and Pancreas Transplantation, University of California, Los Angeles, CA 90095
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24
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VanPatten S, Al-Abed Y. High Mobility Group Box-1 (HMGb1): Current Wisdom and Advancement as a Potential Drug Target. J Med Chem 2018; 61:5093-5107. [PMID: 29268019 DOI: 10.1021/acs.jmedchem.7b01136] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
High mobility group box-1 (HMGb1) protein, a nuclear non-histone protein that is released or secreted from the cell in response to damage or stress, is a sentinel for the immune system that plays a critical role in cell survival/death pathways. This review highlights key features of the endogenous danger-associated molecular pattern (DAMP) protein, HMGb1 in the innate inflammatory response along with various cofactors and receptors that regulate its downstream effects. The evidence demonstrating increased levels of HMGb1 in human inflammatory diseases and conditions is presented, along with a summary of current small molecule or peptide-like antagonists proven to specifically target HMGb1. Additionally, we delineate the measures needed toward validating this protein as a clinically relevant biomarker or bioindicator and as a relevant drug target.
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Affiliation(s)
- Sonya VanPatten
- Center for Molecular Innovation , The Feinstein Institute for Medical Research , 350 Community Drive , Manhasset , New York 11030 , United States
| | - Yousef Al-Abed
- Center for Molecular Innovation , The Feinstein Institute for Medical Research , 350 Community Drive , Manhasset , New York 11030 , United States
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25
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Zaouali MA, Panisello A, Lopez A, Folch E, Castro-Benítez C, Adam R, Roselló-Catafau J. Cross-Talk Between Sirtuin 1 and High-Mobility Box 1 in Steatotic Liver Graft Preservation. Transplant Proc 2017; 49:765-769. [PMID: 28457391 DOI: 10.1016/j.transproceed.2017.01.071] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide +-dependent histone deacetylase that regulates various pathways involved in ischemia-reperfusion injury (IRI). Moreover, high-mobility group box 1 protein (HMGB1) has also been involved in inflammatory processes during IRI. However, the roles of both SIRT1 and HMGB1 in liver preservation is poorly understood. In this communication, we evaluated the potential relationship between SIRT1 and HMGB1 in steatotic and non-steatotic liver grafts preserved in Institute Georges Lopez solution (IGL-1) preservation solution enriched or not enriched with trimetazidine (TMZ). METHODS Steatotic and non-steatotic livers were preserved in IGL-1 preservation solution (24 hours, 4°C), enriched or not enriched with TMZ (10 μmol/L), and then submitted to ex vivo reperfusion (2 hours; 37°C). Liver injury (AST/ALT) and function (bile output, vascular resistance) were evaluated. SIRT1, HMGB1, autophagy parameters (beclin-1, LC3B), PPAR-γ, and heat-shock protein (HO-1, HSP70) expression were determined by means of Western blot. Also, we assessed oxidative stress, mitochondrial damage (glutamate dehydrogenase), and TNF-α levels. RESULTS Elevated SIRT1 and enhanced autophagy were found after reperfusion in steatotic livers preserved in IGL-1+TMZ when compared with IGL-1. However, these changes were not seen in the case of non-steatotic livers. Also, HO-1 increases in the IGL-1 + TMZ group were evident only in the case of steatotic livers, whereas HSP70 and PPAR-γ protein expression were enhanced only in non-steatotic livers. All reported changes were consistent with decreased liver injury diminution, ameliorated hepatic function, and decreased TNF-α and HMGB levels. In addition, the oxidative stress and mitochondrial damage were efficiently prevented by the IGL-1 + TMZ use. CONCLUSIONS SIRT1 is associated with HMGB1 decreases and increased autophagy in steatotic livers, contributing to increased tolerance to cold IRI.
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Affiliation(s)
- M A Zaouali
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain; Research Unit of Biology and Molecular Anthropology Applied to Development and Health (UR12ES11), Faculty of Pharmacy, University of Monastir, Tunisia; High Institut of Biotechnology of Monastir, University of Monastir, Tunisia
| | - A Panisello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain
| | - A Lopez
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Villejuif, France
| | - E Folch
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain
| | - C Castro-Benítez
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Villejuif, France
| | - R Adam
- Centre Hépato-Biliaire, Hôpital Universitaire Paul Brousse, Villejuif, France
| | - J Roselló-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain.
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26
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Inkaya AC, Demir NA, Kolgelier S, Sumer S, Demir LS, Ural O, Pehlivan FS, Aslan M, Arpaci A. Is serum high-mobility group box 1 (HMGB-1) level correlated with liver fibrosis in chronic hepatitis B? Medicine (Baltimore) 2017; 96:e7547. [PMID: 28885322 PMCID: PMC6392731 DOI: 10.1097/md.0000000000007547] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 06/18/2017] [Accepted: 06/26/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND High-mobility group box 1 (HMGB1), identified as an alarmin molecule, was shown to have a role in virus-triggered liver injury. We aimed to evaluate the association between serum levels of HMGB1 and liver fibrosis. METHOD This cross-sectional case-control study included 189 chronic hepatitis B (CHB) patients and 51 healthy controls. All patients underwent liver biopsy and modified Knodell scoring system used to determine the fibrosis level in CHB patients. Serum HMGB1 levels were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS Mean serum HMGB1 levels of patients (58.1 ± 54.7) were found to be higher than those of the control group (7.1 ± 4.3) (P = .001). HMGB1 levels of patients with advanced-stage fibrosis (stage 4 and 5) were detected to be higher than those of patients with early-stage fibrosis (stage 1-3). However, this difference was not statistically significant (P > .05). Albumin levels of fibrosis 3 and 4 patients were lower than fibrosis 1 and 2 patients. ALT, HBV DNA, and AFP levels of fibrosis 5 patients were significantly higher than fibrosis 1 and 2 patients, and their platelet and albumin levels are lower than fibrosis 1 and 2 patients (P < .001). In a logistic regression model, fibrosis levels were correlated with ALT values and inversely correlated with albumin levels. CONCLUSION In this study, we demonstrated that serum HMGB1 levels increase in the early course of liver injury and this increase is not correlated with severity of the liver damage.
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Affiliation(s)
- Ahmet Cagkan Inkaya
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Hacettepe University, Ankara
| | - Nazlim Aktug Demir
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Selçuk University, Konya
| | - Servet Kolgelier
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Adiyaman University, Adiyaman
| | - Sua Sumer
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Selçuk University, Konya
| | - Lutfi Saltuk Demir
- Department of Public Health, Faculty of Medicine, Necmettin Erbakan University, Konya
| | - Onur Ural
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Selçuk University, Konya
| | | | - Mahmure Aslan
- Department of Biochemistry, Adiyaman Education and Research Hospital, Adiyaman
| | - Abdullah Arpaci
- Department of Biochemistry, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey
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27
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Zaouali MA, Panisello-Roselló A, Lopez A, Castro Benítez C, Folch-Puy E, García-Gil A, Carbonell T, Adam R, Roselló-Catafau J. Relevance of proteolysis and proteasome activation in fatty liver graft preservation: An Institut Georges Lopez-1 vs University of Wisconsin appraisal. World J Gastroenterol 2017; 23:4211-4221. [PMID: 28694661 PMCID: PMC5483495 DOI: 10.3748/wjg.v23.i23.4211] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 04/08/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To compare liver proteolysis and proteasome activation in steatotic liver grafts conserved in University of Wisconsin (UW) and Institut Georges Lopez-1 (IGL-1) solutions.
METHODS Fatty liver grafts from male obese Zücker rats were conserved in UW and IGL-1 solutions for 24 h at 4 °Cand subjected to “ex vivo” normo-thermic perfusion (2 h; 37 °C). Liver proteolysis in tissue specimens and perfusate was measured by reverse-phase high performance liquid chromatography. Total free amino acid release was correlated with the activation of the ubiquitin proteasome system (UPS: measured as chymotryptic-like activity and 20S and 19S proteasome), the prevention of liver injury (transaminases), mitochondrial injury (confocal microscopy) and inflammation markers (TNF 1 alpha, high mobility group box-1 (HGMB-1) and PPAR gamma), and liver apoptosis (TUNEL assay, cytochrome c and caspase 3).
RESULTS Profiles of free AA (alanine, proline, leucine, isoleucine, methionine, lysine, ornithine, and threonine, among others) were similar for tissue and reperfusion effluent. In all cases, the IGL-1 solution showed a significantly higher prevention of proteolysis than UW (P < 0.05) after cold ischemia reperfusion. Livers conserved in IGL-1 presented more effective prevention of ATP-breakdown and more inhibition of UPS activity (measured as chymotryptic-like activity). In addition, the prevention of liver proteolysis and UPS activation correlated with the prevention of liver injury (AST/ALT) and mitochondrial damage (revealed by confocal microscopy findings) as well as with the prevention of inflammatory markers (TNF1alpha and HMGB) after reperfusion. In addition, the liver grafts preserved in IGL-1 showed a significant decrease in liver apoptosis, as shown by TUNEL assay and the reduction of cytochrome c, caspase 3 and P62 levels.
CONCLUSION Our comparison of these two preservation solutions suggests that IGL-1 helps to prevent ATP breakdown more effectively than UW and subsequently achieves a higher UPS inhibition and reduced liver proteolysis.
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28
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Shoda LK, Battista C, Siler SQ, Pisetsky DS, Watkins PB, Howell BA. Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses. GENE REGULATION AND SYSTEMS BIOLOGY 2017; 11:1177625017696074. [PMID: 28615926 PMCID: PMC5459514 DOI: 10.1177/1177625017696074] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 02/04/2017] [Indexed: 12/19/2022]
Abstract
Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration. The representation of innate immune responses, detailed here, consolidates much of the available data on the innate immune response in DILI within a single framework and affords the opportunity to systematically investigate the contribution of the innate response to DILI.
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Affiliation(s)
- Lisl Km Shoda
- DILIsym Services, Inc., Research Triangle Park, NC, USA
| | - Christina Battista
- DILIsym Services, Inc., Research Triangle Park, NC, USA.,UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC, USA
| | - Scott Q Siler
- DILIsym Services, Inc., Research Triangle Park, NC, USA
| | - David S Pisetsky
- Medical Research Service, Durham VA Medical Center and Duke University Medical Center, Durham, NC, USA
| | - Paul B Watkins
- UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC, USA
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29
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Sun J, Guo E, Yang J, Yang Y, Liu S, Hu J, Jiang X, Dirsch O, Dahmen U, Dong W, Liu A. Carbon monoxide ameliorates hepatic ischemia/reperfusion injury via sirtuin 1-mediated deacetylation of high-mobility group box 1 in rats. Liver Transpl 2017; 23:510-526. [PMID: 28133883 DOI: 10.1002/lt.24733] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 01/09/2017] [Accepted: 01/14/2017] [Indexed: 12/12/2022]
Abstract
Carbon monoxide (CO) exerts protective effects on hepatic ischemia/reperfusion injury (IRI), but the underlying molecular mechanisms are not fully understood. High-mobility group box 1 (HMGB1) is an important mediator of injury and inflammation in hepatic IRI. Here, we investigated whether CO could attenuate hepatic IRI via inhibition of HMGB1 release, particularly through sirtuin 1 (SIRT1). CO was released by treatment with carbon monoxide-releasing molecule (CORM)-2. CORM-2-delivered CO ameliorated hepatic IRI, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory responses, and less severe ischemia/reperfusion-associated histopathologic changes. Treatment with CORM-2 significantly inhibited IRI-induced HMGB1 translocation and release. SIRT1 expression was increased by CORM-2 pretreatment. When CORM-2-induced SIRT1 expression was inhibited using EX527, HMGB1 translocation and release were increased and hepatic IRI was worsened, whereas SIRT1 activation by resveratrol reversed this trend. In vitro, CORM-2 reduced hypoxia/reoxygenation-induced HMGB1 translocation and release, these inhibitions were blocked by SIRT1 inhibition using EX527 or SIRT1 small interfering RNA both in alpha mouse liver 12 cells and RAW264.7 macrophages. Moreover, SIRT1 directly interacted with and deacetylated HMGB1. IRI increased HMGB1 acetylation, which was abolished by CORM-2 treatment via SIRT1. In conclusion, these results suggest that CO may increase SIRT1 expression, which may decrease HMGB1 acetylation and subsequently reduce its translocation and release, thereby protecting against hepatic IRI. Liver Transplantation 23 510-526 2017 AASLD.
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Affiliation(s)
- Jian Sun
- Department of Biliopancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Enshuang Guo
- Department of Infectious Diseases, Wuhan General Hospital of Guangzhou Military Command, Wuhan, China
| | - Jiankun Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shenpei Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jifa Hu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojing Jiang
- Department of Infectious Diseases, Wuhan General Hospital of Guangzhou Military Command, Wuhan, China
| | - Olaf Dirsch
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University Jena, Jena, Germany
| | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University Jena, Jena, Germany
| | - Wei Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Anding Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University Jena, Jena, Germany
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Kashiwadate T, Miyagi S, Hara Y, Akamatsu Y, Sekiguchi S, Kawagishi N, Ohuchi N, Satomi S. Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1. TOHOKU J EXP MED 2017; 239:315-23. [PMID: 27523810 DOI: 10.1620/tjem.239.315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Transplantation using grafts obtained after cardiac death (CD) is considered a promising solution for graft shortages. However, no standard criteria for organ preservation have been established for CD donors. High-mobility group box 1 (HMGB1) is a DNA-binding protein that is released from dying hepatocytes as an early mediator of inflammation and organ tissue damage. HMGB1 stimulates immunocytes to produce inflammatory cytokines, thereby amplifying the inflammatory response. Thrombomodulin is an integral membrane protein that functions as an endothelial anticoagulant cofactor, and it binds HMGB1 through the extracellular domain. We investigated the effects of ART-123, recombinant human soluble thrombomodulin, on warm ischemia-reperfusion injury in liver grafts. Male Wistar rats were divided into four ex vivo groups: heart-beating (HB) group, in which livers were isolated from HB donors; CD group, in which livers were isolated from CD donors exposed to apnea-induced conditions and warm ischemic conditions for 30 min after cardiac arrest; and two CD groups pretreated with ART-123 (1 or 5 mg/kg). Each isolated liver was reperfused for 1 h after cold preservation for 6 h. The perfusate levels of HMGB1, LDH, TNF-α, and IL-6 were significantly lower in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. Bile production was significantly higher in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. The sinusoidal spaces were significantly narrower in the CD group than in the other groups. We propose that ART-123 maintains sinusoidal microcirculation by reducing endothelial cell damage during warm ischemia-reperfusion injury.
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Affiliation(s)
- Toshiaki Kashiwadate
- Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital
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31
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Zaouali MA, Panisello A, Lopez A, Castro C, Folch E, Carbonell T, Rolo A, Palmeira CM, Garcia-Gil A, Adam R, Roselló-Catafau J. GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation. Int J Mol Sci 2017; 18:ijms18030591. [PMID: 28282906 PMCID: PMC5372607 DOI: 10.3390/ijms18030591] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 02/20/2017] [Accepted: 02/23/2017] [Indexed: 01/07/2023] Open
Abstract
We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia-reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention.
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Affiliation(s)
- Mohamed Amine Zaouali
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain.
- Research Unit of Biology and Molecular Anthropology Applied to Development and Health (UR12ES11), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia.
- High Institute of Biotechnology of Monastir, University of Monastir, Monastir 5000, Tunisia.
| | - Arnau Panisello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain.
| | - Alexandre Lopez
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France.
| | - Carlos Castro
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France.
| | - Emma Folch
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain.
| | - Teresa Carbonell
- Department of Physiology, Faculty of Biology, University of Barcelona, Barcelona 08028, Catalonia, Spain.
| | - Anabela Rolo
- Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal.
| | - Carlos Marques Palmeira
- Center of Neurosciences and Cell Biology, University of Coimbra, Coimbra 3004-504, Portugal.
| | | | - René Adam
- Centre Hépato-Biliaire, AP-PH, Hôpital Paul Brousse, Paris 94804, France.
| | - Joan Roselló-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona 08036, Catalonia, Spain.
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Matta BM, Reichenbach DK, Blazar BR, Turnquist HR. Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses. Am J Transplant 2017; 17:320-327. [PMID: 27232285 PMCID: PMC5124552 DOI: 10.1111/ajt.13887] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 05/18/2016] [Accepted: 05/23/2016] [Indexed: 01/25/2023]
Abstract
Cell damage and death releases alarmins, self-derived immunomodulatory molecules that recruit and activate the immune system. Unfortunately, numerous processes critical to the transplantation of allogeneic materials result in the destruction of donor and recipient cells and may trigger alarmin release. Alarmins, often described as damage-associated molecular patterns, together with exogenous pathogen-associated molecular patterns, are potent orchestrators of immune responses; however, the precise role that alarmins play in alloimmune responses remains relatively undefined. We examined evolving concepts regarding how alarmins affect solid organ and allogeneic hematopoietic cell transplantation outcomes and the mechanisms by which self molecules are released. We describe how, once released, alarmins may act alone or in conjunction with nonself materials to contribute to cytokine networks controlling alloimmune responses and their intensity. It is becoming recognized that this class of molecules has pleotropic functions, and certain alarmins can promote both inflammatory and regulatory responses in transplant models. Emerging evidence indicates that alarmins and their receptors may be promising transplantation biomarkers. Developing the therapeutic ability to support alarmin regulatory mechanisms and the predictive value of alarmin pathway biomarkers for early intervention may provide opportunities to benefit graft recipients.
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Affiliation(s)
- Benjamin M. Matta
- Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Dawn K. Reichenbach
- Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Bruce R. Blazar
- Department of Pediatrics, Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Hēth R. Turnquist
- Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Corresponding author: Hēth R. Turnquist, PhD,
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Siemionow K, Teul J, Drągowski P, Pałka J, Miltyk W. New potential biomarkers of acetaminophen-induced hepatotoxicity. Adv Med Sci 2016; 61:325-330. [PMID: 27471017 DOI: 10.1016/j.advms.2016.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 02/29/2016] [Accepted: 05/16/2016] [Indexed: 12/26/2022]
Abstract
Acetaminophen (APAP) is one of the most common antipyretic and analgesic drugs. Despite various precautions patients use APAP in amounts exceeding acceptable daily doses. APAP overdosing contributes to APAP intoxication, which leads to acute liver injury or necessity of exigent liver transplantation. Biomarkers that can be helpful in early diagnosis of liver injury during APAP overdosing are studied worldwide. This review presents recent reports on new potential biomarkers and their prospective application in clinical practice.
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Omori K, Kobayashi E, Komatsu H, Rawson J, Agrawal G, Parimi M, Oancea AR, Valiente L, Ferreri K, Al-Abdullah IH, Kandeel F, Takahashi M, Mullen Y. Involvement of a proapoptotic gene (BBC3) in islet injury mediated by cold preservation and rewarming. Am J Physiol Endocrinol Metab 2016; 310:E1016-26. [PMID: 27117005 PMCID: PMC4935146 DOI: 10.1152/ajpendo.00441.2015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 03/31/2016] [Indexed: 12/23/2022]
Abstract
Long-term pancreatic cold ischemia contributes to decreased islet number and viability after isolation and culture, leading to poor islet transplantation outcome in patients with type 1 diabetes. In this study, we examined mechanisms of pancreatic cold preservation and rewarming-induced injury by interrogating the proapoptotic gene BBC3/Bbc3, also known as Puma (p53 upregulated modulator of apoptosis), using three experimental models: 1) bioluminescence imaging of isolated luciferase-transgenic ("Firefly") Lewis rat islets, 2) cold preservation of en bloc-harvested pancreata from Bbc3-knockout (KO) mice, and 3) cold preservation and rewarming of human pancreata and isolated islets. Cold preservation-mediated islet injury occurred during rewarming in "Firefly" islets. Silencing Bbc3 by transfecting Bbc3 siRNA into islets in vitro prior to cold preservation improved postpreservation mitochondrial viability. Cold preservation resulted in decreased postisolation islet yield in both wild-type and Bbc3 KO pancreata. However, after culture, the islet viability was significantly higher in Bbc3-KO islets, suggesting that different mechanisms are involved in islet damage/loss during isolation and culture. Furthermore, Bbc3-KO islets from cold-preserved pancreata showed reduced HMGB1 (high-mobility group box 1 protein) expression and decreased levels of 4-hydroxynonenal (4-HNE) protein adducts, which was indicative of reduced oxidative stress. During human islet isolation, BBC3 protein was upregulated in digested tissue from cold-preserved pancreata. Hypoxia in cold preservation increased BBC3 mRNA and protein in isolated human islets after rewarming in culture and reduced islet viability. These results demonstrated the involvement of BBC3/Bbc3 in cold preservation/rewarming-mediated islet injury, possibly through modulating HMGB1- and oxidative stress-mediated injury to islets.
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Affiliation(s)
- Keiko Omori
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California;
| | - Eiji Kobayashi
- Center for Development of Advanced Medical Technology and Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan
| | - Hirotake Komatsu
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Jeffrey Rawson
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Garima Agrawal
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Mounika Parimi
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Alina R Oancea
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Luis Valiente
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Kevin Ferreri
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Ismail H Al-Abdullah
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Fouad Kandeel
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
| | - Masafumi Takahashi
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; and
| | - Yoko Mullen
- Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Duarte, California
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Lea JD, Clarke JI, McGuire N, Antoine DJ. Redox-Dependent HMGB1 Isoforms as Pivotal Co-Ordinators of Drug-Induced Liver Injury: Mechanistic Biomarkers and Therapeutic Targets. Antioxid Redox Signal 2016; 24:652-65. [PMID: 26481429 DOI: 10.1089/ars.2015.6406] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
SIGNIFICANCE High-mobility group box 1 (HMGB1) is a critical protein in the coordination of the inflammatory response in drug-induced liver injury (DILI). HMGB1 is released from necrotic hepatocytes and activated immune cells. The extracellular function of HMGB1 is dependent upon redox modification of cysteine residues that control chemoattractant and cytokine-inducing properties. Existing biomarkers of DILI such as alanine aminotransferase (ALT) have limitations such as lack of sensitivity and tissue specificity that can adversely affect clinical intervention. RECENT ADVANCES HMGB1 isoforms have been shown to be more sensitive biomarkers than ALT for predicting DILI development and the requirement for liver transplant following acetaminophen (APAP) overdose. Hepatocyte-specific conditional knockout of HMGB1 has demonstrated the pivotal role of HMGB1 in DILI and liver disease. Tandem mass spectrometry (MS/MS) enables the characterization and quantification of different mechanism-dependent post-translationally modified isoforms of HMGB1. CRITICAL ISSUES HMGB1 shows great promise as a biomarker of DILI. However, current diagnostic assays are either too time-consuming to be clinically applicable (MS/MS) or are unable to distinguish between different redox and acetyl isoforms of HMGB1 (ELISA). Additionally, HMGB1 is not liver specific, so while it outperforms ALT (also not liver specific) as a biomarker for the prediction of DILI development, it should be used in a biomarker panel along with liver-specific markers such as miR-122. FUTURE DIRECTIONS A point-of-care test for HMGB1 and the development of redox and acetyl isoform-targeting antibodies will advance clinical utility. Work is ongoing to validate baseline levels of circulating HMGB1 in healthy volunteers.
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Affiliation(s)
- Jonathan D Lea
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool , Liverpool, United Kingdom
| | - Joanna I Clarke
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool , Liverpool, United Kingdom
| | - Niamh McGuire
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool , Liverpool, United Kingdom
| | - Daniel J Antoine
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool , Liverpool, United Kingdom
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Pharmacological Modulation of Ischemic-Reperfusion Injury during Pringle Maneuver in Hepatic Surgery. A Prospective Randomized Pilot Study. World J Surg 2016; 40:2202-12. [DOI: 10.1007/s00268-016-3506-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Braza F, Brouard S, Chadban S, Goldstein DR. Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nat Rev Nephrol 2016; 12:281-90. [PMID: 27026348 DOI: 10.1038/nrneph.2016.41] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances--damage-associated molecular patterns (DAMPs)--that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients.
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Affiliation(s)
- Faouzi Braza
- Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 2780-156 Oeiras, Portugal
| | - Sophie Brouard
- INSERM, UMR 1064, CHU de Nantes, ITUN, 30 Bd Jean Monnet Nantes F-44093, France
| | - Steve Chadban
- Renal Medicine and Transplantation, Royal Prince Alfred Hospital, Missenden Road Camperdown, NSW 2050, Sydney, Australia.,Kidney Node, Charles Perkins Centre, University of Sydney, Missenden Road, Camperdown, NSW 2093, Australia
| | - Daniel R Goldstein
- Department of Internal Medicine, 333 Cedar St, Yale School of Medicine, New Haven, Connecticut 06525, USA.,Department of Immunobiology, 300 Cedar St, Yale School of Medicine, New Haven, Connecticut 06525, USA
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Circulating Fibroblast Growth Factor 21 Is A Sensitive Biomarker for Severe Ischemia/reperfusion Injury in Patients with Liver Transplantation. Sci Rep 2016; 6:19776. [PMID: 26806156 PMCID: PMC4726235 DOI: 10.1038/srep19776] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 11/05/2015] [Indexed: 02/07/2023] Open
Abstract
Hepatic ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality after liver surgery. Therefore, it is important to identity reliable biomarkers to assist early diagnosis of hepatic I/R injury. This study aimed to investigate the potential of serum levels of fibroblast growth factor 21 (FGF21) as a biomarker for hepatic I/R injury in patients with liver transplantation. Two independent cohorts of liver transplantation patients were recruited for determination of serum levels of FGF21, ALT, and AST. The results demonstrated that serum FGF21 at 2 hours post-reperfusion in cohort-1 exhibited an approximately 20-fold elevation relative to those in healthy subjects. In blood samples dynamically collected in cohort-2, a dramatic increase in serum FGF21 levels (~25-fold) was observed at two hours after surgery, whereas the peak levels of serum ALT and AST were detected only after 24 hours. Temporal correlation analysis demonstrated a significant association of peak serum levels of FGF21 at 2 hours with the magnitude of the increase in both serum ALT and AST levels at 24 hours post transplantation. In conclusion, serum FGF21 may represent a sensitive and specific prognostic biomarker for early detection of I/R injury in patients with liver transplantation.
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HMGB1 Promotes Hepatitis C Virus Replication by Interaction with Stem-Loop 4 in the Viral 5' Untranslated Region. J Virol 2015; 90:2332-44. [PMID: 26656705 DOI: 10.1128/jvi.02795-15] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 12/04/2015] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED High-mobility group box 1 (HMGB1) protein is a highly conserved nuclear protein involved in multiple human diseases, including infectious diseases, immune disorders, metabolic disorders, and cancer. HMGB1 is comprised of two tandem HMG boxes (the A box and the B box) containing DNA-binding domains and an acidic C-terminal peptide. It has been reported that HMGB1 enhances viral replication by binding to viral proteins. However, its role in hepatitis C virus (HCV) replication is unknown. Here, we show that HMGB1 promoted HCV replication but had no effect on HCV translation. RNA immunoprecipitation experiments indicated that the positive strand, not the negative strand, of HCV RNA interacted with HMGB1. HCV infection triggered HMGB1 protein translocation from the nucleus to the cytoplasm, in which it interacted with the HCV genome. Moreover, the A box of HMGB1 is the pivotal domain to interact with stem-loop 4 (SL4) of the HCV 5' untranslated region. Deletion of the HMGB1 A box abrogated the enhancement of HCV replication by HMGB1. Our data suggested that HMGB1 serves as a proviral factor of HCV to facilitate viral replication in hepatocytes by interaction with the HCV genome. IMPORTANCE Hepatitis C virus (HCV) is a major global health threat, affecting more than 170 million people infection worldwide. These patients are at high risk of developing severe liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Currently, no vaccine is available. Many host factors may be implicated in the pathogenesis of HCV-related diseases. In this study, we found a novel HCV RNA-binding protein, HMGB1, that promotes HCV RNA replication. Moreover, SL4 in the 5' untranslated region of the HCV genome is the key region for HMGB1 binding, and the A box of HMGB1 protein is the functional domain to interact with HCV RNA and enhance viral replication. HMGB1 appears to play an important role in HCV-related diseases, and further investigation is warranted to elucidate the specific actions of HMGB1 in HCV pathogenesis.
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Impact of Donation Mode on the Proportion and Function of T Lymphocytes in the Liver. PLoS One 2015; 10:e0139791. [PMID: 26513368 PMCID: PMC4626218 DOI: 10.1371/journal.pone.0139791] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 09/17/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Liver T-cells respond to the inflammatory insult generated during organ procurement and contribute to the injury following reperfusion. The mode of liver donation alters various metabolic and inflammatory pathways but the way it affects intrahepatic T-cells is still unclear. METHODS We investigated the modifications occurring in the proportion and function of T-cells during liver procurement for transplantation. We isolated hepatic mononuclear cells (HMC) from liver perfusate of living donors (LD) and donors after brain death (DBD) or cardiac death (DCD) and assessed the frequency of T-cell subsets, their cytokine secretion profile and CD8 T-cell cytotoxicity function, responsiveness to a danger associated molecular pattern (High Mobility Group Box1, HMGB1) and association with donor and recipient clinical parameters and immediate graft outcome. RESULTS We found that T-cells in healthy human livers were enriched in memory CD8 T-cells exhibiting a phenotype of non-circulating tissue-associated lymphocytes, functionally dominated by more cytotoxicity and IFN-γ-production in DBD donors, including upon activation by HMGB1 and correlating with peak of post-transplant AST. This liver-specific pattern of CD8 T-cell was prominent in DBD livers compared to DCD and LD livers suggesting that it was influenced by events surrounding brain death, prior to retrieval. CONCLUSION Mode of liver donation can affect liver T-cells with increased liver damage in DBD donors. These findings may be relevant in designing therapeutic strategies aimed at organ optimization prior to transplantation.
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A facilitated method for hepatic vein blood: sampling during liver transplantation. Transplantation 2015; 99:e25-6. [PMID: 25827323 DOI: 10.1097/tp.0000000000000637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Autophagy and liver ischemia-reperfusion injury. BIOMED RESEARCH INTERNATIONAL 2015; 2015:417590. [PMID: 25861623 PMCID: PMC4377441 DOI: 10.1155/2015/417590] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 08/21/2014] [Accepted: 09/07/2014] [Indexed: 12/12/2022]
Abstract
Liver ischemia-reperfusion (I-R) injury occurs during liver resection, liver transplantation, and hemorrhagic shock. The main mode of liver cell death after warm and/or cold liver I-R is necrosis, but other modes of cell death, as apoptosis and autophagy, are also involved. Autophagy is an intracellular self-digesting pathway responsible for removal of long-lived proteins, damaged organelles, and malformed proteins during biosynthesis by lysosomes. Autophagy is found in normal and diseased liver. Although depending on the type of ischemia, warm and/or cold, the dynamic process of liver I-R results mainly in adenosine triphosphate depletion and in production of reactive oxygen species (ROS), leads to both, a local ischemic insult and an acute inflammatory-mediated reperfusion injury, and results finally in cell death. This process can induce liver dysfunction and can increase patient morbidity and mortality after liver surgery and hemorrhagic shock. Whether autophagy protects from or promotes liver injury following warm and/or cold I-R remains to be elucidated. The present review aims to summarize the current knowledge in liver I-R injury focusing on both the beneficial and the detrimental effects of liver autophagy following warm and/or cold liver I-R.
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Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ, Lotze MT, Tang D. HMGB1 in health and disease. Mol Aspects Med 2014; 40:1-116. [PMID: 25010388 PMCID: PMC4254084 DOI: 10.1016/j.mam.2014.05.001] [Citation(s) in RCA: 731] [Impact Index Per Article: 66.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/05/2014] [Indexed: 12/22/2022]
Abstract
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
| | - Ruochan Chen
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Qiuhong Zhang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Wen Hou
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Sha Wu
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yan Yu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhengwen Yan
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Xiaofang Sun
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Experimental Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China
| | - Haichao Wang
- Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Qingde Wang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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Abstract
High-mobility group box 1 (HMGB1) was originally defined as a ubiquitous nuclear protein, but it was later determined that the protein has different roles both inside and outside of cells. Nuclear HMGB1 regulates chromatin structure and gene transcription, whereas cytosolic HMGB1 is involved in inflammasome activation and autophagy. Extracellular HMGB1 has drawn attention because it can bind to related cell signalling transduction receptors, such as the receptor for advanced glycation end products, Toll-like receptor (TLR)2, TLR4 and TLR9. It also participates in the development and progression of a variety of diseases. HMGB1 is actively secreted by stimulation of the innate immune system, and it is passively released by ischaemia or cell injury. This review focuses on the important role of HMGB1 in the pathogenesis of acute and chronic sterile inflammatory conditions. Strategies that target HMGB1 have been shown to significantly decrease inflammation in several disease models of sterile inflammation, and this may represent a promising clinical approach for treatment of certain conditions associated with sterile inflammation.
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Affiliation(s)
- A Tsung
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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de Souza A, Westra J, Bijzet J, Limburg PC, Stegeman CA, Bijl M, Kallenberg CGM. Is serum HMGB1 a biomarker in ANCA-associated vasculitis? Arthritis Res Ther 2014; 15:R104. [PMID: 24007972 PMCID: PMC3978820 DOI: 10.1186/ar4284] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 05/29/2013] [Accepted: 09/04/2013] [Indexed: 12/20/2022] Open
Abstract
Background Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic inflammatory disorders that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), Churg-Strauss syndrome and renal limited vasculitis (RLV). Extracellular high-mobility group box 1 (HMGB1) acts as an alarmin and has been shown to be a biomarker of disease activity as well as an autoantigen in systemic lupus erythematosus (SLE) and, possibly, in AAV. This study aims to assess antibodies against HMGB1 and HMGB1 levels as biomarkers for AAV disease activity and predictors of relapsing disease. Methods AAV patients with active disease and healthy controls (HC) were evaluated for anti-HMGB1 antibodies while serum HMGB1 levels were measured longitudinally in AAV patients at presentation, during remission, prior to and at relapses. Results HMGB1 levels were similar between AAV patients at presentation (n = 52) and HC (n = 35) (2.64 ± 1.80 ng/ml vs. 2.39 ± 1.09 ng/ml; P = 0.422) and no difference regarding HMGB1 levels could be found among AAV disease subsets (GPA: 2.66 ± 1.83 ng/ml vs. MPA: 3.11 ± 1.91 ng/ml vs. RLV: 1.92 ± 1.48 ng/ml; P = 0.369). AAV patients with renal involvement had lower HMGB1 levels than patients without renal involvement at presentation (2.35 ± 1.48 ng/ml vs. 3.52 ± 2.41 ng/ml; P = 0.042). A negative correlation was observed between HMGB1 levels and 24-hour proteinuria (ρ = -0.361, P = 0.028). Forty-nine AAV patients were evaluated for HMGB1 levels during follow-up and no differences were observed between relapsing and nonrelapsing patients (P = 0.350). No significant increase in HMGB1 levels was observed prior to a relapse compared with the remission period and changes in HMGB1 levels were not associated with an increased risk for relapse in AAV. Positivity for anti-HMGB1 antibodies was low in patients with active AAV (three out of 24 patients). Conclusions Serum HMGB1 levels at presentation are not increased and are lower in patients with renal involvement. Relapses are not preceded or accompanied by significant rises in HMGB1 levels and changes in HMGB1 levels are not related to ensuing relapses. Anti-HMGB1 antibodies are present in only a few patients in AAV. In contrast to SLE, HMGB1 is not a useful biomarker in AAV.
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Kuroda N, Inoue K, Ikeda T, Hara Y, Wake K, Sato T. Apoptotic response through a high mobility box 1 protein-dependent mechanism in LPS/GalN-induced mouse liver failure and glycyrrhizin-mediated inhibition. PLoS One 2014; 9:e92884. [PMID: 24690901 PMCID: PMC3972228 DOI: 10.1371/journal.pone.0092884] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 02/26/2014] [Indexed: 12/31/2022] Open
Abstract
HMGB1 is a nuclear component involved in nucleosome stabilization and transcription regulation, but extracellularly it is able to serve as a potential late mediator of lethality. In the present study, we explored inflammation-promoting activity of HMGB1 and blockade of extracellular release of HMGB1 by glycyrrhizin (GL) in LPS/GalN-triggered mouse liver injury. At 1 to 10 h after LPS/GalN-treatment, mice were anesthetized to collect blood from heart puncture, and serum transaminase and HMGB1 were evaluated. Administration of LPS/GalN precipitated tissue injury associated with time-dependent alteration in HMGB1 serum levels. At 8 h nuclear immunoreactive products were remarkably reduced and extracellular HMGB1 expression was found exclusively in the pericentral foci. The treatment with GL significantly down-regulated the serum levels of ALT, AST, and HMGB1 in addition to the strong inhibition of tissue injury and extracellular immunoreactivity to HMGB1 and to acetylated-lysine. Furthermore, GL brought about a significant decrease in the number of apoptotic hepatocytes labeled with TUNEL-method. On the basis of these results, three apoptosis-associated genes were identified with microarray analysis and real-time PCR. The ChIP-assay revealed the binding of HMGB1 protein to Gsto1 promoter sequence in LPS/GalN-treated mice and the remarkable decrease in combined HMGB1 protein by GL. The current findings claim that a single injection of LPS/GalN might stimulate apoptosis of hepatocytes through the binding of HMGB1 protein to Gsto1 promoter region and that GL-treatment might prevent the apoptosis and inflammatory infiltrates caused with LPS/GalN-injection by disturbing the binding of HMGB1 protein to Gsto1 promoter sequence.
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Affiliation(s)
- Noriyuki Kuroda
- Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Kouji Inoue
- Research Center of Electron Microscopy, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Tadayuki Ikeda
- Department of Geriatric Dentistry, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Yaiko Hara
- Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Japan
| | - Kenjiro Wake
- Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Japan
- Liver Research Unit, Minophagen Pharmaceutical Co. Ltd., Tokyo, Japan
| | - Tetsuji Sato
- Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Japan
- * E-mail:
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Craig DG, Lee P, Pryde EA, Hidalgo E, Hayes PC, Wigmore SJ, Forbes SJ, Simpson KJ. Markedly Increased High-Mobility Group Box 1 Protein in a Patient with Small-for-Size Syndrome. Case Rep Transplant 2014; 2014:272498. [PMID: 24600525 PMCID: PMC3926239 DOI: 10.1155/2014/272498] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 12/09/2013] [Indexed: 02/07/2023] Open
Abstract
Background. Small-for-size syndrome (SFSS) occurs in the presence of insufficient liver mass to maintain normal function after liver transplantation. Murine mortality following 85% hepatectomy can be reduced by the use of soluble receptor for advanced glycation end products (sRAGE) to scavenge damage-associated molecular patterns and prevent their engagement with membrane-bound RAGE. Aims. To explore serum levels of sRAGE, high-mobility group box-1 (HMGB1) protein, and other soluble inflammatory mediators in a fatal case of SFSS. Methods. Serum levels of HMGB1, sRAGE, IL-18, and other inflammatory mediators were measured by ELISA in a case of SFSS, and the results were compared with 8 patients with paracetamol-induced acute liver failure (ALF) and 6 healthy controls (HC). Results. HMGB1 levels were markedly higher in the SFSS patient (92.1 ng/mL) compared with the ALF patients (median (IQR) 11.4 (3.7-14.8) ng/mL) and HC (1.42 (1.38-1.56) ng/mL). In contrast, sRAGE levels were lower in the SFSS patient (1.88 ng/mL) compared with the ALF patients (3.53 (2.66-12.37) ng/mL) and were similar to HC levels (1.40 (1.23-1.89) ng/mL). Conclusion. These results suggest an imbalance between pro- and anti-inflammatory innate immune pathways in SFSS. Modulation of the HMGB1-RAGE axis may represent a future therapeutic avenue in this condition.
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Affiliation(s)
- Darren G. Craig
- 1Gastroenterology Department, The James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK
- *Darren G. Craig:
| | - Patricia Lee
- 2Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
| | - E. Anne Pryde
- 2Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
| | - Ernest Hidalgo
- 3Adult and Paediatric Liver Services, St James's University Hospital, Leeds LS9 7TF, UK
| | - Peter C. Hayes
- 2Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
| | - Stephen J. Wigmore
- 2Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
| | - Stuart J. Forbes
- 4MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Kenneth J. Simpson
- 2Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK
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Chen R, Hou W, Zhang Q, Kang R, Fan XG, Tang D. Emerging role of high-mobility group box 1 (HMGB1) in liver diseases. Mol Med 2013; 19:357-66. [PMID: 24306421 DOI: 10.2119/molmed.2013.00099] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 11/05/2013] [Indexed: 12/13/2022] Open
Abstract
Damage-associated molecular pattern (DAMP) molecules are essential for the initiation of innate inflammatory responses to infection and injury. The prototypic DAMP molecule, high-mobility group box 1 (HMGB1), is an abundant architectural chromosomal protein that has location-specific biological functions: within the nucleus as a DNA chaperone, within the cytosol to sustain autophagy and outside the cell as a DAMP molecule. Recent research indicates that aberrant activation of HMGB1 signaling can promote the onset of inflammatory and autoimmune diseases, raising interest in the development of therapeutic strategies to control their function. The importance of HMGB1 activation in various forms of liver disease in relation to liver damage, steatosis, inflammation, fibrosis, tumorigenesis and regeneration is discussed in this review.
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Affiliation(s)
- Ruochan Chen
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wen Hou
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Qiuhong Zhang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Xue-Gong Fan
- Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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Zhao H, Watts HR, Chong M, Huang H, Tralau-Stewart C, Maxwell PH, Maze M, George AJT, Ma D. Xenon treatment protects against cold ischemia associated delayed graft function and prolongs graft survival in rats. Am J Transplant 2013; 13:2006-18. [PMID: 23710625 PMCID: PMC3884761 DOI: 10.1111/ajt.12293] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Revised: 03/18/2013] [Accepted: 04/04/2013] [Indexed: 01/25/2023]
Abstract
Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia-hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival.
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Affiliation(s)
- H Zhao
- Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster HospitalLondon, UK
| | - H R Watts
- Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster HospitalLondon, UK
| | - M Chong
- Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster HospitalLondon, UK
| | - H Huang
- Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster HospitalLondon, UK
| | - C Tralau-Stewart
- Department of Medicine, Drug Discovery Centre, Imperial College LondonLondon, UK
| | - P H Maxwell
- Division of Medicine, University College LondonLondon, UK
| | - M Maze
- Department of Anesthesia and Perioperative Care, University of CaliforniaSan Francisco, CA
| | - A J T George
- Section of Molecular ImmunologyDepartment of MedicineImperial College London, Hammersmith HospitalLondon, UK
| | - D Ma
- Department of Surgery and Cancer, Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea & Westminster HospitalLondon, UK,Department of Anesthesiology, Hubei University of MedicineHubei, China,*Corresponding author: Daqing Ma,
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